A lingering conundrum of the immune response is how do certain immune/inflammatory cells remember whether or not they should be actively transcribing specific genes, which would facilitate their participation in a given inflammatory response. Our laboratory is investigating novel epigenetic changes, induced via post- translational modifications of histones, as mechanisms to regulate the expression profiles of immune cell derived mediators, during the initiation and maintenance of lung inflammation. We have found that in the presence of either Th1 or Th2 type cytokines dynamic acetylation and/or methylation events occur at the amino terminus of histones H3 and H4, which directly regulate chromatin structures dictating the accessibility of transcription factors to specific promoters. In this application we will utilize established models of lung inflammation, which possess a distinct Th1 or Th2 phenotype, to investigate cytokine-directed, novel epigenetic-based mechanisms that direct the immune cell phenotype in support of lung pathology. Our preliminary data support a key role for epigenetic mechanisms in maintaining the inflammatory phenotype. We hypothesize that during the maintenance of pulmonary disease, a polarized cytokine environment that dictates the phenotype of specific immune cell subpopulations directly induces specific epigenetic changes in the cells, which in turn maintain cell specific transcription program required for disease chronicity. This hypothesis will be investigated via the following specific aims: 1) To investigate cell specific epigenetic changes, which are governed by the dominant cytokine environment associated with a Th1 or a Th2 type pulmonary immune response, 2) To examine the mechanistic role of the histone methyl transferase, MLL, and the histone demethylase, JMJD3, on the development of a Th1 or Th2 dependent pulmonary inflammation using conditional knockout mouse models, and 3) To assess the cytokine-induced JAK-STAT signal transduction pathways that control MLL and JMJD3 expression and influence the subsequent immune response. Our proposed studies provide an innovative approach by assessing the epigenetic-based mechanisms that control the sustained inflammatory phenotype associated with chronic lung inflammation and provide an opportunity for the development of new biomarkers and novel, efficacious therapies.